Dr. John Dick awarded Premier's Summit Award.
Funding from the Province of Ontario intended to recognize extraordinary research, support expansion of research programs and catalyze commercialization.
The A-Team of Stem Cell Science.
A Globe and Mail article from November 25, 2006 provides a historical perspective on the cancer stem cell model developed by Dr. John Dick and other Toronto-based scientists.
Cancer: The root of the problem.
Dr. John Dick's pioneering work on leukemia stem cells is referred to in the August 17, 2006 issue of Nature's Web Focus.
“If cancer stem cells lie at the heart of some cancers, then being able to predict the behavior of tumors and providing effective therapies against them means understanding the abnormal growth pathways within the stem cells themselves.”
- John Dick, Project Leader (UHN)
“The only reason that I'm willing to take a risk on this project is my confidence in the quality and camaraderie of my colleagues.”
- Scott Tanner, Principal Investigator (University of Toronto)
“We're examining DNA not for its well-recognized role as the genetic material to store and transmit genetic information, but rather for its less-known potential to act as a novel cancer diagnostic tool.”
- Yingfu Li, Principal Investigator (McMaster University)
“We're gaining more understanding of cell defects and how to modify them, so that treatment is no longer a shotgun approach, but more like an arrow aimed at a specific target.”
- Mark Minden, Principal Investigator (OCI)
project overview
Mass spectrometer-based flow cytometer, methods and applications:
Developing tools to identify rare cancer cells
The Problem: Cancer is a Stem Cell Disease, and Stem Cells are Rare
There is mounting evidence that many types of cancer, including leukemia, are stem cell diseases. Researchers have found that a tumour's development is sustained, not by the majority of cells that comprise the tumour's bulk, but by the few cancer stem cells at its root. These cancer stem cells (CSCs), representing far less than one percent of the cells in a tumour (approximately one in a million), drive the tumour's growth, immortality and malignancy. As a result, accurate predictions of the behaviour of a tumour depend on careful analysis of the abnormal growth pathways within the CSCs. Similarly, effective treatment requires identification and eradication of the specific CSCs that are present in the patient. This Genome Canada project, led by Dr. John Dick, is developing tools both to identify the rare cancer stem cells in patient samples, and to examine the cancer pathways within leukemic stem cells.
Like the proverbial needle in a haystack, stem cells are very rare, and difficult to isolate by conventional approaches. In order to detect CSCs, we will develop a newly configured ICP-MS instrument, a suite of affinity products (antibodies or aptamers), and a protocol that will allow rapid and serial analysis of the CSCs (the needles) in a cohort of cells (the haystack), by exploiting their unique cellular properties.
Figure 1: Schematic of the concept of the Mass Spectrometer-based Flow Cytometer. A cell contains many thousands of proteins. It is reasonable to expect that a cell of interest has certain protein "markers" that distinguish that type of cell from other cells in the sample (perhaps by the presence or the concentration or the ratio of the marker proteins). An affinity product (antibody or aptamer) that has been tagged with a specific element binds to the protein marker. When the cell is introduced into the ICP, it is atomized and ionized. The elemental composition of the cell, including the tagged affinity products that are bound to the protein markers, is measured. The presence and intensity of the signals corresponding to the tags on the affinity products indicates the presence of the biomarkers on that cell. The distribution and concomitance of those signals can be used to confirm that the cell was sampled; if the markers have been appropriately selected, the measurement could be diagnostic.
The Solution: Finding the Stem Cell Fingerprints
All cells contain many thousands of proteins and the combination of proteins within each cell (or cell type) can define the biological properties of that cell. As a result, it is reasonable to expect that a cell of interest (like the CSC) has certain protein biomarkers that will distinguish it from the other cells in a sample.
In our approach, a set of affinity products (that have each been tagged with a unique element) binds to the protein biomarkers of a cell. When the cell is introduced into the ICP-MS, it is atomized and ionized. The elemental composition of the tagged affinity products that are bound to the biomarkers is determined. The presence, ratio and intensity of the signals corresponding to the elemental tags represent the distribution of the biomarkers on that cell, acting as a cellular "fingerprint". If the fingerprint of the CSC is known, it can be used to identify any CSCs amongst the other cell types in the patient's sample.
The Approach: Creating a New Toolbox
Our interdisciplinary group will address the significant challenge of identifying Leukemic Stem Cells (LSCs) in patient samples by collaborating to accomplish four central tasks. The tasks, divided by research group, are as follows:
1. John Dick's Lab (UHN): Separate and purify (to the extent currently possible) Leukemic Stem Cells (LSCs) and their healthy counterparts, Hematopoetic Stem Cells (HSCs). Identify affinity products (antibodies) that can uniquely identify normal and diseased stem cells.
2. Yingfu Li's Lab (McMaster): Select a suite of highly-specific, non-cross reactive affinity products (aptamers) that can uniquely identify LSCs, and label these aptamers with stable, isotopic, elemental tags that can be detected by the ICP-MS based flow cytometer.
3. Scott Tanner's Lab (University of Toronto): Develop a novel Inductively Coupled Plasma Mass Spectrometer (ICP-MS) dedicated to discrete particle assay in a flow cytometer configuration.
4. Mark Minden's Lab (OCI/UHN): Collect and characterize the clinical patient samples that will be used to validate the instrument and application. Investigate the genomic and proteomic distinctions of leukemia.
To find out more about the role of each group in this Genome Canada project, please click on the name of the principal investigator.
